Cardiac calsequestrin (CASQ2), and its binding partners junctin and triadin-1 (TRDN), are key regulators of sarcoplasmic reticulum (SR) Ca2+ storage and release. In humans, CASQ2 mutations cause a syndrome of catecholaminergic polymorphic ventricular tachycardia and sudden cardiac death. To determine the mechanisms whereby CASQ2 mutations cause electrophysiologic instability but preserve contractile function, we have generated Casq2 null (Casq2-/-) mice. Our preliminary studies demonstrate that despite a lack of Casq2 protein, these mice maintain near normal SR Ca2+ storage, possibly as a result of an expansion of SR volume and drastic reductions in the Casq2 binding proteins triadin-1 and junctin. Casq2-/- mice phenocopy the human CASQ2- linked arrhythmias by developing polymorphic ventricular tachycardia with catecholamine infusion or exercise. Casq2-/- myocytes display premature spontaneous SR Ca2+ releases resulting in after- contractions and triggered beats. Significantly, commonly-used antidepressant drugs, which disrupt Ca2+ binding to CASQ2 in vitro, have also been linked to an increased incidence in sudden cardiac death, raising the possibility of a Casq2-linked form of drug-induced arrhythmias, analogous to the drug-associated long QT syndrome. Based on these human genetic, epidemiological, and mouse data, we hypothesize that disruption of Casq2 causes dysfunctional SR Ca2+ release and contributes to arrhythmia susceptibility and sudden death. To test our central hypothesis, we will examine single cell, whole heart and in vivo electrophysiology, contractile function, Ca2+ homeostasis, protein expression and SR ultrastructure in Casq2-/- , Casq2+/-, triadin-1 null (Trdn-/-) and selectively cross-bred animals. Our goals are to test the individual contribution of Casq2 and triadin-1 to arrhythmia susceptibility and further elucidate the molecular and cellular mechanism(s) that lead to ventricular arrhythmias in response to inherited and possibly drug-induced Casq2 dysfunction. The outcome of this research will not only advance our understanding of the pathophysiology of inherited arrhythmia syndromes, but also help unravel the mechanism(s) responsible for sudden deaths linked to antidepressant medications taken by millions of patients.